15-methyl and 15-ethyl prostaglandin analogs

ABSTRACT

Prostaglandin E and F compounds with a methyl or an ethyl substituent at the C-15 position are disclosed. These are useful for the same pharmacological purposes as the unsubstituted prostaglandins.

United States Patent [119] Bundy 1 Apr. 17,1973

[ IS-METHYL ANDls-ETHYL [56] References-Cited: I

I PROSTAGLANDIN ANALOGS FOREIGN PATENTS OR APPLICATIONS [75] Inventor: Gordon L. Bundy, Kalamazoo v A Township Kalamazoo y 1,533,808 6/1968 France "260/468 Mlch- OTHER PUBLICATIONS [731 Assigneefi. fif Cmlmy, Kalamazm, Corey etal.,J.A.C.S. 91, 5678 (1969) Schneider, Chem. c6m.'1.969 304 A [22] Filed; May 4, 1970 Fieser et aL, Reagents for Org. Syn. pp. 415, 416, 420, 21 Appl. N6.=.34,51s 1235(1968) v v v 7 Primary Examiner-Lorraine A. Weinberger [52 us. c1 ..260/s14 D, 260/50 1.15, 260/501.l7, AssistamEmminer Roben Germ 260/5012,424/305,424/317, 260/211, Am) "8 Earl C S eth and John K h 260/2472 R, 260/268 R, 260/293.65, pa e 260/3263, 260/429.9,' 260/430, 260/439 R, I

260/448 R; 260/448.8 R, 260/468 D, [57] ABSTRACT v I CI I 9 Prostaglandin E and F Compounds with a methyl 01- an I] .L c Field ofSea -ch ..260 468, 514 ethyl subsumem at the C45 are d'sclosed' These are useful for the same pharmacological put poses as the unsubstituted prostagla'ndins.

3 Claims, N0 DI-awings IS-METI-IYL AND IS-ETI-IYL PROSTAGLANDIN ANALOGS DESCRIPTION OF THE INVENTION This invention relates to novel compositions of matter, to novel methods for producing those, and to novel chemical intermediates useful in those processes.

In particular, this invention relates to novel derivatives of prostanoic acid which has the following structure and atom numbering:

6 4 2 COOH 9 8 7\A\A\A 10 14 1s 1s 20 I Various derivatives of prostanoic acid are known in the art. ,These are called prostaglandins. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited-therein. For example, prostaglandin E, (PGE,) has the following structure: I

Dihydroprostalandin E (dihydr0-PGE,) has the following structure:

E H6 II 011 Prostaglandins with a secondary alpha or beta hydroxy in place of the ring oxo of the prostaglandins E are also known. These are called prostaglandins F, For example, prostaglandin F a (F'GF a has the following structure:

COOH

Prostaglandin F B (PGF B has the following structure:

H VII Prostaglandins F01 and F B corresponding to PGE,, PGE and dihydro-PGE, are also known.

In formulas I] to VII, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring. The sidechain hydroxy at C-1 5 in formulas II to VII is in S configuration. See Nature, 212, 38 (l966)'for discussion of the stereochemistry of the prostaglandins. v

Molecules of the known prostaglandins each have several centers ofasymmetry, and can exist in racemic.

(optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e., the dextrorotatory and levorotatory forms. As drawn, formulas II to VII each represent the particular optically active form of the prostaglandin which is obtained from certain mam- The racemic form of a prostaglandin would contain equal numbers of both enantiomeric molecules, and

one of formulas II to VII and the mirror image of that formula would both be needed to represent correctly the corresponding racemioprostaglandin. For convenience hereinafter, use of the terms PGE PGE PGE dihydro-PG'E FGF tr PGF a POE, a

dihydro-PGF B will mean the optically active form of "that prostaglandin with the same absolute configuration as PGE obtained from mammalian tisstiesQWhen reference to the racemic I form of one of those prostaglandins is intended, the word racemic will preceed the prostaglandin name, thus, racemic PGE or racemic PGF a Each of the novel prostanoic acidderivatives of this invention is encompassed by one of the following formulas or by the combination of'that formula and its mirror image:

X ll 000R;

R1 0H vm X H M00011,

11o 1:, on 1x XII XIII

In formulas VIII to XIII, R is hydrogen, alkyl of one to eight carbon atoms, inclusive, or a pharmacologically acceptable cation, R is methyl or ethyl, and X is x0, alpha hydroxy, or beta hydroxy, i.e., =0, v H

' I or g In formulas VIII, X, and XII, theconfiguration of the hydroxy at C-1 5 is S as in the known prostaglandins of formulas II to VII. In formulas IX, XI, and XIII, the hydroxy at C-l5 is in the unnatural R configuration. .See J. Chem. Education, 41, l 16 (I964), for discussion of S and R configurations.

A significant characteristic of all of the known pr'ostaglandins is the secondary hydroxy group at C-1 5, I

- i.e., the atom grouping grouping or thecorresponding R configuration grouping It: on

wherein R, is methyl or ethyl. Thus, these novel prostanoic acid derivatives may conveniently be figuration as PGE, obtained from mammalian tissues.-

Except for the compounds encompassed by formulas XI and XII, the novel prostanoic acid derivatives of this invention also include the corresponding racemic compounds. One of formulas VIII, IX, X, or XI plus the mirror image of that formula are necessary in combinationto describe a racemic compound. For convenience hereinafter, when the word racemic receedsthe name of one of the novel prostanoic acid derivatives of this invention, the intent is to designate a racemic compound represented by the combination of the 'appropriate formula VIII to XI and the mirror imageof that formulav When. the word racemic" doesnot preceed the compound name, the intent is to designate an optically active compound represented only by the appropriate formula VIII to' XI and with the same absolute configuration as PGE obtained from animal tissues. Novel prostanoic acid derivatives of thisinvention encompassed by formulas XII and XIII are limited to optically active compounds.

PGE POE- PGEg, dihydro-PGE,, and the corresponding PGF (1 and PGF compounds, and their esters and pharmaco-logically acceptable salts are eittremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example ,'l3ergstrom et al., Pharmacol. Rev. 20, I (1968), and. references cited therein. A few of those biological responses are,

systemic arterial blood pressure lowering in the case of the PGE and PGF [3 compounds as measured, for example, in anesthetized (pentobarbital sodium) pentolinium-treated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for the PGF compounds; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbitgduodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-inducedmo bilization of free fatty acids or inhibition. of'the spontaneous release of glycerol from isolated rat fat pads;

inhibition of gastric secretion in the case of the PGE compounds as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical 'stinuli, c.g.; arterial injury, and various biochemical stimuli, e. g., ADP, ATP,serotonin thrombin, and collage'mand in the case of the PGE compounds, stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and'ra skin segments. Because of these biological responses, these known protaglandins are useful to study, prevent, control, or alleviate a wide variety of diseasesand undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, and especially the PGE compounds, are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about ug. to about l0 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

The PGE compounds are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 ug. 'to' about 500 pg. per kg. of body weight per minute, or in a total daily dose by injection'or infusion in the range about 0.1 to about mg. per kg. ofbody Weight per day, the exact dose depending on the age, weight, and condition of'the patient or animal, and on the frequency and route of administration.

The PGE, PGF a and PGF B compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as athercosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action.

,For rapid response, especially in emergency situations,

the intravenous route of administration is preferred. Doses in the range about 0.005 to about-20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGE, PGF 0 and PGF B compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoidedby the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, 'to the blood of the donor animal, to the'perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

abortion or delivery, to aid in expulsion of the placenta,

and during the puerperium. For the latter purpose, the PGE compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 pg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneoils, or intramuscular-injection or infusion during puer- .perium in the range 0.01 to 2-mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal. 1

The PGE and PGF [3 compounds are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 ug. per kg. of body weight per minute, or in singleor multiple doses of about 25 to 500 pg. per kg. of body weight total per day.

The PGE, PGF a and PGF B compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose 0.01 to 50 pg. per kg. ofbody weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one ormore weeks postmature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started.

The PGF a PGF [3 and PGE compounds are useful for controlling the reproductive cycle inovulating female mammals, including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. For that purpose, PGE or PGF a., for example, is administered systemically, e.g., intravenously, subcutaneously, and intravaginally, at a dose level in the range 0.001 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during'a span of time starting approximately at the time of ovulation and ending approximately at the ,next expected time of menses or just prior to that time. Additionally, expulsion of an embryo or fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.

As mentioned above, the PGE compounds are potent antagonists of epinephrine-induced mobilization offree fatty acids. For this reason, thiscompoundis useful in experimental medicine for both in vitro and in vivo stu dies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure. of diseases involving abnormal lipid mobilization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism. 1

The novel l-methyl and l5-ethyl prostaglandin analogs encompassed by formulas VIII to XIII and also the-corresponding R and S l5-methyl and IS-ethyl PGE PGF; 0: and PGF, B compounds each cause .the same biological responses described above for the potent and has a substantially longer duration of activity. For that reason, fewer and smaller doses of these prostaglandin analogs are needed to attain the desired pharmacological results.

The novel PGE-type,.PGF -type, and PGF ,8 -type analogs encompassed by formulas VIII to XIIIand also the correspond-ing Rand S PGE PGF oz and PGF B analogs are used as described above in free acid form,

in alkyl ester form, or in pharmacologically acceptable salt form. When the ester form is used, any alkyl ester can be used wherein the alkyl moiety contains one to .eight carbon atoms, inclusive,i.e., methyl, ethyl,

propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. However, it is preferred that the ester be alkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl, and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system.

Pharmacologically acceptable salts of these prostaglandin analogs useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations arethose derived from the alkali metals, e.g., lithium,'sodium and potassium, and'from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, B-phenylethylamine, ethylenediamine, diethylenetriamine,

and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., lmethylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2-methylpyrrolidine, l ,4-dimethylpiperazine, 2-niethylpiperidine,

' and the like,as 'well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and

'the free acid form or the pharmacologically acceptable salt form. For subcutaneous or intramuscular injection,

sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration, suppositories, tampons, ring devices, and preparations adapted to generate sprays or foams or to be used for lavage, all prepared as known in the art, are used. For tissue implants, a sterile tablet orsilicone rubber capsule or other object containing'or impregnated with the substance is used.

The novel PGE-type acids and alkyl esters of formulas VIII to XIII wherein X is =0, and also thecorresponding R and S PGE -type acids and alkyl esters are prepared by oxidation of the corresponding PGF, a-type or PGF ,B-type acids and alkyl estrsIFor this purpose, an oxidizing agent is used which selectively oxidizes secondary hydroxy groups tocarbonyl groups in the presence of carbon-carbon double. bonds. These transformations are shown in Chart A, wherein formulas XIV and XV include optically active compounds as shown and racemic compounds of those formulas'and' the mirror images thereof, and'also the IS-epimers of both of those, i.e., wherein the configuration at C-1 5 is For the transformations of Chart A, the betaisomers of reactants XIV and XVI are-preferred starting materials, although the corresponding-alpha isomers are also useful for this purpose. I 1

Oxidation reagents useful for the transformations set forth in ChartA are'known to the art. An especially useful reagent for this purpose is the Jones reagent, i.e., acidified chromic acid. See J. Chem. Soc. 39 (I946). Acetone is a suitable diluent for this purpose, anda slight excess beyond theamount necessary to oxidize one of the secondary hydroxy g'roups'of the formula XIV orXVI reactant is used. Reaction temperatures at least as low as about 0 C. should be used. Preferred R2 011 XIV l (Oxidation) 0 O a OlIz-Y(OHz)g- OR4 XC(OH2)rClI HO R2 011 XV MA 116 l R2 011 xvr l (Oxidation) I coon; /uZ/WA no m on XVII product is isolated by conventional methods.

Examples of other oxidation reagents useful for the Chart A transformations are silver carbonate on Celite (Chem. Commun. 1102 (1969)), mixtures of chromium trioxide and pyridine (Tetrahedron Letters 3363 (1968), J. Am. Chem. Soc. 75, 422 (1953), and Tetrahedron, 18, 1351 (1962)), mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide (J. Am. Chem. Soc. 89, 5505 (1967)), and mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am.Chem.Soc. 87,5661 (1965)).

The novel PGF -type and PGF -type acids and esters of formulas VIII to XIII wherein X is and also the corresponding PGF, oz-type and PGFI B-type acids and alkyl esters are prepared by the sequence of transformations shown in Charts B and C, wherein formulas XVIII, XIX, XX, XXI, and XXII include optically active compounds as shown and racemic compounds of those formulas and the mirror images thereof, and wherein formulas XXIII, XXIV,

XXV, XXVI, and XXVII are limited to the optically active compounds as shown. Also in Charts B and C, R is methyl or ethyl, R is hydrogen or alkyl of one to eight carbon atoms, inclusive, X and Y are both CH CI-l or X is trans--CH==CI-I and Y is --CH CI-I or cis-Cl-I=CH-, and indicates attachment of hydroxy to the ring in alpha or beta configuration. Also in Charts B and C, A is alkyl of one to four carbon atoms, inclusive, aralkyl of seven to l2 carbon atoms, inclusive, phenyl, or phenyl substituted with one or two fluoro, chloro, or alkyl of one to four carbon atoms, in-

clusive, and R is alkyl of one to eight carbon atoms, in-

clusive, or Si--(A) wherein A is as defined above.

CHART B XXII OOORI H OH XXIII l (oxidation) Ho I MACOORI Ho XXIV l tsilylation) Quasi- (Ah-SPO I XXV l RzMgX l (hydrolysis) no R2 OH XXVI XXVII The various A of a Si (A) moiety are alike or different. For example, an -Si (A);, can be trimethylsilyl, dimethylphenylsilyl, ormethylphenylbenzylsilyl. Examples of alkyl of one to four carbon atoms, inclusive, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Examples of aralkyl of seven to 12 carbon atoms, inclusive, are benzyl, phenethyl, a-phenylethyl, 3-phenylpropyl, a-naphthylmethyl, and 2-(B- naphthyl.)ethyl. Examples of phenyl substituted with one or 2 fluoro, chloro, or alkyl of one to four carbon atoms inclusive, are p-chlorophenyl, m-fluorophenyl, ostolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4- chIoro-2-methylphenyl, and 2,4-dichloro-3- methylphenyl.

In Charts B and C, the final PGF and PGF B products are those encompassed by formulas XXI XXII and XXVI XXVII, respectively.

The initial optically active reactants of formulas XVIII and XXIII in Charts B and C, i.e., PGF,a, PGF, 3 PGF, 0: PGF, #1 POP}, 01 FOR, ,8 dihydro-PGFm and .dihydro-PGF, l3 and their alkyl esters are known in the art or are prepared by methods known in the art.

See, for example, Bergstrom et al., cited above, US. Pat. No. 3,069,322, and British specification No. 1,040,544. The initial racemic reactants of formula XVIII in Chart B, i.e., racemic PGF, 0: racemic PGF B racemic PGF l1 and racemic PGF B and their alkyl esters are known in the art or are prepared by 'methods known in the art. See, for example, Just et al.,

J. Am. Chem. Soc. 91, 5364 (1969), Corey et al., J. Am. Chem. Soc. 90, 3245 (1,968), and Schneider et al., Chemical Communications (Great Britain), 304 (I969).

Racemic dihydro-PGF, and racemic dihydro- PGF B and their esters are prepared by catalytic hydrogenation of the corresponding racemic PGF, or PGF and PGF B or PGF B compounds, respectively, for example, in the presence of 5 percent palladium-on-charcoal catalyst in ethyl acetate solution at 25 C. and one atmosphere pressure of hydrogen. Racemic PGF and racemic PGF B and their alkyl esters are not yet known in'the art.

The known acids and esters of formulas XVIII and.

XXIII are transformed to the corresponding intermediate l5-oxo acids and estersof'formulas. XIX and XXIV, respectively, by oxidation with reagents such as 2,3-dichloro-5 ,6-dicyanol ,4-benzoquinone, activated manganese dioxide, or nickelperoxide (see Fieser et al., Reagents for Organic Synthesis, John Wiley & Sons, Inc., New York, N.Y., pp 215, 637,, and 731) Alternatively, and especially for the formula XVIII reactants wherein X and Y are C'I-I CH these oxidations are carried out by oxygenation in the presence of the IS-hydroxyprostaglandin dehydrogenase .of swine lung (see Arkiv for Kemi 25, 293 (1966)). These reagents are used according to procedures known in the art. See, for example, J. Biol. Chem. 239, 4097 (1964). Referring again to Charts B and C, the intermediat compounds of formulasXIX and XXIV are trans- I formed to silyl derivatives of formulas XX and XXV, respectively, by procedures known in the art. See, for example, Pierce, .Silylation or Organic Compouncls, Pierce Chemical Co., Rockford, Ill. (1968). Both hydroxy groups of the formula XIX or XXIV reactants" are thereby transformed to --OSi- (A.) moieties wherein A is as definedvabove, and sufficient of the si-. lylating agent is used for that purpose-according to known procedures. When R in the formula XIX or XXIV intermediate is hydrogen, the -COOH moiety thereby defined is simultaneously transformed to COOSi-(A) additional silylating agent being used for this purpose. This latter transformation is aided by excess silylating agent and prolonged treatment. When R in formulas XIX and XXIV is alkyl, then R in formulas XX and XXV will also be alkyl. The necessarysilylating agents for thesetransformations are known in the art or are prepared by methods knownin the art.

See, for example, Post, Silicones and Other Organic procedure for Grignard reactions, using diethyl ether as a reaction solvent and saturated aqueous ammonium chloride solution to hydrolyze the Grignard complex. The resulting disilyl or trisilyl tertiary alcohol is then hydrolyzed with water to remove the silyl groups. For this purpose, it is advantageous to use a mixture of water and sufficient of a water-miscible solvent, e.g., ethanol to give a homogenous reaction mixture. The hydrolysis is usually complete in 2 to 6 hours at 25 C., and is preferably carriedout in an atmosphere of an inert gas, e.g., nitrogen or argon.

The mixture of 15-8 and l-R isomers obtained by this Grignard reaction and hydrolysis is separated by procedures known in the art for separating mixtures of prostanoic acid derivatives, for example, by chromatography on neutral silica gel. In some instances, the lower alkyl esters, especially the methyl esters of a pair of 1558 and l5-R isomers is more readily separated by silica gel chromatography than are the corresponding acids. In those cases, it is advantageous to esterify the mixture of acids as described below, separate the two esters, and then, if desired, saponify the esters by procedures known in the art for saponification of prostaglandins F.

Although formula XXI and XXII compounds wherein X and Y are both CH CH are produced according to the processes of Chart B, it is preferred to produce those novel dihydro-PGF, analogs by hydrogenation of one of the corresponding unsaturated compounds, i.e., a compound of formula XXI or XXII wherein X is trans-CH=CH and Y is CH CH or cis-CH=CI-I, or a compound offormula XXVI or XXVII. This hydrogenation 'is advantageously carried out catalytically, for example, in the presence of a 5 percent palladium-on-charcoal catalyst in ethyl acetate solution at 25 C. and one atmosphere pressure of hydrogen.

As discussed above, the processes of Charts A, B,

, and C lead either to acids (R, is hydrogen) or to alkyl esters (R, is alkyl of one to eight carbon atoms, inclusive). When a formula XXI, XXII, XXVI, XXVII PGF- type acid or a formula XV or XVII POE-type acid (Chart A) has been prepared and an alkyl ester is desired, esterification is advantageously accomplished by interaction of the acid with the appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane, and l-diazo-2-ethylhexane, for example, gives the ethyl, butyl, and 2-ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contct of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reactions, John Wiley & Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 I954).

An alternative method for esterification of the carboxyl moiety of the PGF-type or PGE-type compounds comprises transformation of the free acid to the corresponding silver salt, followed by interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, and the like. The silver salts are prepared by conventional methods, for example, by dissolving theacid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometric amount of silver nitrate.

The novel formula VIII to XIII acids (R is hydrogen) are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium, salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding .to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt of the prostanoic acid derivative. Evaporation of the water or addition of a water-miscible solvent of moderate polari ty, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acid is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of theamine corresponding to the desired cation is then added'to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixing the acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.

The invention can be more fully understoodby the following examples.

Infrared absorption spectra are recordedon a Perkin-Elmer model 42l infrared spectrophotometer. Un-

diluted (neat) samples of the liquids and oils are used.

Mineral oil (Nujol) mulls of the solids are used.

NMR spectra are recorded on a Varian A-60 spectrophotometer with tetramethylsilane as an internal e.g., l5-oxo-PGF refers to a prostaglandin analog wherein the moiety tered.

Example 1 15-Oxo-PGF a 2,3-Dichloro- ,6-dicyano-1,4-benzoquinone (463 mg.) is added to a solution of PGF (600 mg.) in 30 ml. of dioxane. The mixture is stirred 24 hours at 50 C. under nitrogen, and then is cooled to C. and fil- The filtered solids are washed with dichloromethane. Evaporation of the combined filtrate and washings at reduced pressure gives 650 mg. of a residue which is chromatographed on 150 g. of silica Example 2 l5-Oxo-PGF, 13

2,3-Dichloro-S,6-dicyano-1,4-benzoquinone 1.0 g.) is added to a solution of PGF, B (1.3 g.) in 80 m1. of dioxane. The mixture is stirred 24 hours at 50 C. under nitrogen, and ,is then cooled to 20 C. and filtered. The

filtered solids are washed with dichloromethane.. Evaporation of the combined filtrate and washings at v reduced pressure gives 1.6 g. of a residue which is chro- 'matographed on 400 g. of silica gel (Silicar CC-4; Mallincrodt), eluting with 75 percent ethyl acetate in Skel- 16 Also following the procedure of Example 1, the racemic forms ofPGF, a PGF, [3 PGF, 0: PGF, [3 POP}, 01 PGF B and the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those are each oxidized to the correspondingracemic 15-oxo compound.

Example 7 Dihydro- 1 S-oxo-PGF 1 a Following the procedure of Arkiv for Kemi, 25, 293 (1966), dihydroPGF a' is oxidized to dihydro-lS- oxo-PGF, a with the dehydrogenase enzyme of swine lung.

Following the procedure of Example 7, dihydro- PGF, B is oxidized to dihydro-lS-oxo-PGF, B

Also following the procedure of Example 7, the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of dihydro-PClvF a and dihydro-PGF, are each oxidized to the corresponding 15-oxo compounds.

Also following the procedure of Example 7, the racemic forms of dihydro-PGF, o1 dihydro-PGF, B and the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those are each oxidized to the corresponding racemic 15-oxo compound.

Example 8 Tris-(trimethylsilyl) Derivatives of 15-" Oxo-PGF, a. A mixture of hexamethyldisilazane (11 ml.) and trimethylchlorosilane (2.2 ml.) is added to a solution of 15-oxo-PGF, a (545 mg.) in 55 m1. of tetrahydrofuran. This mixture is stirred 16 hours at 25 C. .under nitrogen, and is then filtered. The filtrate is evaporated lysolve B. Evaporation of the eluates gives 1.15 g. of

l5-oxo-PGE B infrared absorption at 3,380, 2,660, 1,720, 1,705, 1,665, 1,620,. 1,460, 1,405, 1,370, 1,325, 1,285, 1,235,1,190, 1,080, 1,040, and 980 6111- Example 3 15-Oxo-PGF a Following the procedure of Example 1, PGF a is oxidized to l5-oxo-PGF o1 infrared absorption at 3,400, 2,660, 1,705, 1,660, 1,625,],405, 1,375, 1,320, 1,290, 1,245l ,225, 1,2151,175, 1,115, 1,075, 1,050, and 980 cm".

Following the procedure of Example 1, PGF B is oxidized to 15-oxo-PGF B infrared absorption at 3,380, 3,010, 2,650, 1,705, 1,655, 1,625, 1,320, 1,295, 1,245-1,225, 1,190, 1,085, 1,040, and 980 cm".

Example 4 Following the procedure of Example 1, FOR, B is oxidized to 15-oxo-PGF B Also following theprocedure of Example 1, the

8 methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of PGF, 0: POE/3 PGF, :1 PGF- B POE, and PGF; B are each oxidized to the corresponding 15-oxo compounds.

Example 9 Tris-(trimethylsilyl) Der1vatives of 15- Oxo-PGF, 6

Following the procedure of Example 8, l5-oxo-1GF B is transformed to the tris-(trimethylsilyl) derivativej infrared absorption at 1,725, 1,680, 1,635, 1,375, 1,250,

1,180, 1,065, 980, 840, and 750 cm'.

Example 10 Tris-(trimethylsilyl) Derivative of 15- Oxo-PGF a 0 Example 11- Tris-(trimethylsilyl)Derivative of 15- Oxo-PGF, ,8. I i

Following the procedure of Example 8, 1 5-oxo -PGF B is transformed to the tris-(trimethylsilyl) derivative; infrared absorption at 1,725, 1,680, 1,635 l,250,'and 845 cm".

Example 12 Tris-(trimethylsilyl) Derivative of 15- Oxo-PGF a Following the procedure of Example 8, l5-oxo-PGF a is transformed to the tris-(trimethylsilyl) derivative.

l5-hydroxyprostaglandin Example 13 Tris-(trimethylsilyl) Derivative of 15- Oxo-PGF B Following the procedure of Example 8, l5-oxo-PGF B is transformed to thetris-(trimethylsilyl) derivative.

Example 14 Tris-(trimethylsilyl) Derivative of Dihydrol 5-oxo-PGF, a

Following the procedure of Example 8, dihydro-l5- oxo-PGF, a is transformed to the tris-(trimethylsilyl) derivative.

Example 14A Tris-(trimethylsilyl) Derivative of Dihydro-15-oxo-PGF -B oxo-PGF, fl and the methyl, ethyl, tert-butyl, and 2- ethylhexyl esters of each of those are each transformed to trimethylsilyl derivatives, the acids to tris derivatives and the esters to bis derivative.

.Also following the procedure of Example 8 but using appropriate reactants in place of the hexamethyldis- -i1azane and trimethylchlorosilane, there are prepared IS-MethyLPGF a and lS-Methyl- 15(R) PGF a A 3 molar diethylether solution of methylmagnesium bromide (0.55 ml.) is added dropwise toa stirred solution of thetris-(trimethylsilyl) derivative of 15- oxo-PGF, a (850 mg.) in 25 ml. of diethyl ether at 25 C. The mixture is stirred 30 minutes at 25 C., after which an additional 0.2 ml. of the methylmagnesium Example 15 bromide solution is addedand stirring is continued an additional 30 minutes. The resulting reaction mixture is poured into 75 ml. of saturated aqueous ammonium chloride solution at C. After stirring several minutes, the mixture is extracted repeatedly. with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of the diethyl ether gives a yellow oil (910mg) which is dissolved'in 45 m1. of ethanol. That solution is diluted with 30 ml. of water, and the mixture is stirred 4 hours at 25 C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is saturated with sodium chloride and then extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to give 640 mg. of a mixture of methyl-PGF a and 15-methyl-15(R)-PGF, a infrared absorption at 3,280, 2,600, and 1,710 cm.

Themixture of 15-methy1-PGF a and IS-methyl- 15(R)-PGF a is dissolved in 50 ml. of diethyl ether and cooled to 0 C. Excess diazomethane dissolved in' diethyl ether is then added, and the mixture is maintained 5 minutes at 0 C. and then 5 minutes at C. The solution is evaporated in a stream'of nitrogen, and the residue is chromatographed on 550 g. of neutral silica, eluting with 75 percent ethyl acetate in Skellysolve 8. Evaporation ofeluate fractions gives, successively, 127 mg. of 15-methyl-15(R)-PGF methyl ester,

150 mg. of a mixture of 15-methy1-15(R)-PGF a methyl ester and lS-methyl-PGF, methyl ester, and 228 mg. of l5-methyl-PGF methylester. The latter crystallizes on standing; m.p. 7275 C.; mass spectral molecular ion peaks at 366, 348, 317, 313, and 294.

Aqueous potassium hydroxide solution (45 percent 0.9 ml.) is added to a solution of l5-methyl-PGF a methyl ester (228 mg.) in a mixture of 6.8 ml. .of

methanol and 2.2 ml. of .waterunder nitrogen. The

resulting solution is stirred 2 hours at 25 C., and is then poured into several volumes of water. The aqueous mixture is extracted with ethyl acetate, acidified with3 N hydrochloric acid, saturated'with sodium chloride, and then extracted repeatedly with ethyl acetate. The latter ethyl acetate extracts are combined, washed successively with water and saturated aqueous sodium chloride-solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. The crystalline residue is recrystallized from a mixture of ethyl acetate and Skellysolve B to give IS-methyl-PGF a m.p. 81 -83 C.; infrared absorption at 3,410, 3,300, 2,650, l,705,-1,305, 1,290, 1,275, 1,255, 1,220, 1,195, 1,125, 1,075,. 980, and 915 v cm" NMR peaks (dimethylforrnamide) at'5 .5 a'nd'4 .43 .6 (multiplet) 8; mass spectral molecular ionpeaks at 643, 587,- and 568.

Following the above procedure,- l5-methyl-15 R)- PGF, 0! methyl ester is saponified to 1.5+methyl-15(R)- PGF infrared absorption at 3,380, 2,650, 1,710, 1,460, 1,410, 1,375, l,275l,200, 1,125, 1,075, 1,040,

and 975cm"; NMR peaks (dimethylforma-mide) at 5.50 and 4.40-3.60 (multiplet) 8; mass spectra] molecular ion peaks at,3 52, 334, 316, and 263 Example 16 15-Methy1-PGF,' p and (R P a additonal 15 minutes. The resulting reaction mixture is' poured into a mixture ofice'and ml. of saturated aqueous ammonium'chloride solution. After stirring IS-Methylseveral minutes, the mixture is extracted repeatedly with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of the diethyl ether at reduced pressure gives a colorless, viscous oil which is dissolved in 30 ml. of ethanol. That solution is diluted with 20 ml. of water, and the mixture is stirred 3 hours at 25 C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is diluted with an equal volume of saturated aqueous sodium chloride solution and then extracted repeatedly with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated at reduced pressure to give 700 mg. of acrystalline mixture of IS-methyl-PGF, B and 15-methy1-l-5(R)-PGF,B Recrystallization of this Example 1715-Methyl-PGF a and l-Methyl-15(R)- PGF2 "Following the procedure of Example 15, the tris-(trimethylsilyl) derivative of -oxo-PGF a (500 mg.) is

. transformed first to a mixture of IS-methyl-PGF v1 and l5-methyl-l5(R)-PGF a and then to the corresponding mixture of methyl esters. This methyl ester mixture (520 mg.) is'chromatographed on 500 g. of neutral silica gel (Merck), eluting successively with 2 l.

of percent, 6 l. of 40 percent, and 8 l. of 50 percent "ethyl acetate in Skellysolve B. The corresponding elua'tes'emerging from the column are discarded. Elution iscontinued successively with gradients of 4 l. of 50 percent and 4 l. of 60 percent ethyl acetate in Skellysolve B, and 5 1. of 60 percent and 5 l. of 75 percent ethyl acetate in Skellysolve B, and then with 4 l. of 75 percent ethyl acetate in Skellysolve B, collecting the corresponding eluates in 500-ml. fractions. Elution is further continued successively with 5 l. of 75 percent ethyl acetate in Skellysolve B and with 6 l. of 100 percent ethyl acetate, collecting the corresponding eluates in ZOO-ml. fractions. Eluate fractions 29-35 are combined and evaporated to give 109 mg. of lS-methyll5(R)-PGF a methyl ester. Eluate fractions 39-67 are combined and evaporated to give 155 mg. of 15- methyl-PGF, a methyl ester.

Following the procedure of Example 15, 1'5-methyl- PGF, a methyl ester is saponified to give l5-methyl- PGF, 1! infrared absorption at 3,260, 2,600, 1,710, 1,365, 1,235, 1,040, and 970 cm NMR peaks (deuterochloroform) at 5.82, 5.65-5.15 (multiplet), and 4.2-3.8 8; mass spectral molecular ion peaks at 350, 332,and3l4.

Also following the procedure of Example 15, 15- methyl-l5(R)-PGF a methyl ester is saponified to 15- methyl-l5(R)-PFD a infrared absorption at 3,250, 2,600, 1,710, 1,235, 1,040, and 970 cm; NMR peaks (deuterochloroforrn) at 6.15 (singlet), 4.20-3.8 tiplet), and 0.90 (triplet).

Example 18 l5-Methyl-PGF Band l5-Methyl-.

Following the procedure of Example 15, the tris-(trimethylsilyl) derivative of l5-oxo-PGF B (5.1 g.) is reacted with a total of 8 m1. of 3 molar methylmagnesium bromide in diethyl ether, and the product is hydrolyzed to give a mixture of IS-methyl-PGF and l5-methyl-15(R)-PGF B (4.37 g.) in the form of a dark oil. Crystallization of this oil from a mixture of methanol and ethyl acetate, and recrystallization of the resulting crystals from a mixture of the same solvents gives l5-methyl-PGF B m.p. 134-l,34.5 C.; infrared absorption at 3,250, 3,180, 2,720, 1,710, 1,345, 1,305, 1,235, 1,085, 1,050, 970, and 920 cm ;'NMR peaks (dimethylsulfoxide) at 5.46 (doublet), 5.0-4.0,

and 3.8 (multiplet) 5; mass spectral molecular ion peaks at 368, 350, 332, 314, 297, 278, and 205.

l5-Methyl-l5(R)-PGF B is obtained from the mother liquors of the above crystallization and recrystallization of l5-methyl-PGF B Example 19 15-Methyl-PGF a and IS-Methyl- Example 20 IS-MethyLPGF B and l5-Methyl-l5(R.)

PGF B.

Following the procedure of Example 15, the tris-( trimethylsilyl) derivative of 15-oxo-PGF B is reacted with methylmagnesium bromide,and the product is hydrolyzed to give a mixture of l5-methyl-PGF B and l5-methyl-l5(R)-PGF 3 B Thismixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 1S.'Alternatively, the mixture of acids is separated as described in Example 16.

Example 21 DihydrO-IS-Methyl-PGF a and Dihydrol5-Methyl-l5(R)-PGF a Following the procedure of Example 15, the tris-(trimethylsilyl) derivative of dihydro-lS-oxo-PGF is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of dihydro-lS- methyl-PGF, a and dihydro-15-methyl-15(R)-PGF a This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 15. Alternatively, the mixture of acids is separated as described in Example 16.

(mul- I Example 22 Dihydrol S-Methyl-PGF; [3 and Dihydrol5-Methyl-l5(R)-PGF, 3

Following the procedure of Example 15, the tris-(trimethylsilyl) derivative of dihydro-lS-oxo-PGF B is reacted with methylmagnesium bromide, and the product is hydrolyzed to give a mixture of dihydro-l5- methyl-PGF, B and dihydro-l5-methyl-l5(R)-PGF B This mixture is converted to the corresponding mixture of methyl esters which are separated by chromatography and saponified as described in Example 15. Alternatively, the mixture of acids is sepatated as described in Example 16.

Following the procedure of Example 15, the methyl, ethyl, tert-butyl, and Z-ethyl-hexyl esters of the his- (trimethylsilyl) derivatives of l5-oxo-PGF a l5-oxo- PGF, 6 l5-oxo-PGF 1x l5-oxo-PGF l5-oxoand dihydro-lS-oxo-PGF B are each transformed to the corresponding l5-methyl and l5-methyl-15(R) esters.

Also following the procedure of Example 15, the racemic forms of the trimethylsilyl derivatives of 15- oxo-PGF, a l5-oxo-PGF /3 15-oxo-PGF a 15- oxo-PGF B 15-oxo-PGF a l5.-oxo-PGF B dihydro-lS-oxo-PGF, a dihydro-lS-oxo-PGF, and the methyl, ethyl, tert-buty1, and 2-ethylhexyl esters of each of those, tris derivatives of the acids and bis derivatives of the esters, are each transformed to the corresponding 15-methyl and l5-methyl-l5(R) acid or ester.

Also following the procedure of Example 15, the tris- (triphenylsilyl) and tris-(tribenzylsilyl) derivatives. of l5-oxo-PGF a l5-oxo-PGF B l5-oxo-PGF a l5-oxo-PGF B l5-oxo-PGF 15-oxo-PGF {3 dihydro-l 5-oxo-PGF and dihydro-lS-oxo-PGF B and of the racemic forms of each of those optically active acids, and also the bis-(triphenylsilyl) and bis- (tribenzylsilyl) derivatives of the corresponding methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of' each of those optically active and racemic acids are each transformed to the corresponding l5-methyl and l5-methyl-15(R) acid or ester.

Also following the procedure of Example 15 but using ethylmagnesium bromide in place of the methyl-. magnesium bromide, the tris-(trimethylsilyl), tris- (triphenylsilyl), and the tris-(tribenzylsilyl) derivatives of l5-oxo-PGF a l5-oxo-PGF B l5-oxo-PGF a l5-oxo-PGF a l5-oxo-PGF 3 ,6 dihydro-lS-oxo- POP, 01 dihydro-lS-oxo-PGF B, and the racemic forms of each of those optically active acids, and also the bis-(trimethylsilyl), bis-(triphenylsilyl), and bis- (tribenzylsilyl) derivatives of the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those optically active and racemic acids are each transformed to the corresponding l5-e thyl and 15-ethyl-l5(R) acid or ester.

' 'Example 23 IS-MethyI-PGE A solution of 15-methyl-PGF I3 (95 mg.) in 40 ml. of acetone is cooled to 10 C. Jones reagent (0.1 ml. of a solution of 21 g. of chromic anhydride, 60 ml. of water, and 17 ml. of concentrated sulfuric acid), precooled to C., is added with vigorous stirring. After minutes at C., thin layer chromatography on silica gel (acetic acidzmethanokchloroform; 5:5:90) of a small portion of the reaction mixture indicates about 50 percent reaction completion. An additional 0.06 ml. of Jones reagent is added to the still cold reaction mixture with stirring, and the mixture is stirred an additional 5 minutes at l0 C. Isopropyl alcohol (1 ml.) is added to the cold reaction mixture. After 5 minutes, the mixture is filtered through a layer of diatomaceous silica (Celite). The filtrate is evaporated at reduced pressure, and the residue is mixed with 5 ml. of saturated aqueous sodium chloride solution. The mixture is extracted repeatedly with ethyl acetate, and the combined extracts are washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated at reduced pressure. The residue is chromatographed on 20g. of neutral silica gel, eluting with 50 percent ethyl acetate in Skellysolve-B. Evaporation of the eluates'gives 29 mg. of

l5-methyl-PGE,; mass spectral molecular ion peaks at 350, 332, 317, and 261.

Example 24 lS-Methyl-PGE A solution of l5 methyl-PGF I3 (300 mg.) in 100 ml. of acetone is cooled to 35 C. Jones reagent (0,2

ml.) is added with vigorous stirring, and stirring is continued for 15 minutes. At that point, thin layer chromatography on silica gel (acetic acide:methanolzchloroform; 5:5:90) of a small portion of the reaction mixture indicates about 75 percent reaction complettion. An additional 0.1 ml. of Jones reagent is added to the reaction mixture and stirring is continued at 35 C. for a total reaction time. of minutes. Isopropyl alcohol (1 ml.) is added to the cold reaction mixture which is then allowed to warm to 0 C. and is filtered through Celite. The filtrate is evaporated at reduced pressure, and the residue is dissolved in dichloromethane. That solution is washed with saturated aqueous sodium chloride solution, dried with an-, hydrous sodium sulfate, and evaporated at reduced pressure. Each mg. of residue is chromatographed on a thin layer plate (20 X 20 cm; with a 1000 p. layer of neutral silica gel), developing twice with the A-IX solvent system. The silica gel areas containing the desired product as shown by small-scale thin layer.

Example 25 15-Methy1-PGF Following the procedure of Example 24, 15-methyl- PGFQ B is oxidized to l5-methyl-PGF v Example 26 Dihydro IS-Methyl-PGE,

Following the procedure of Example 24', dihydro-15- methyl-PGF, ii. is oxidized to dihydro-lS-methyl- PGE Example 27 lS-Methyl- 1 5(R)-PGE Following the procedure of Example 24, l5-methyll5(R)-PGF l3 isoxidized to l5-methyl-15(R).-PGE,.

' l(R)-PGF, a lS-methyl- Example 28 l5-Methyl-l5(R)- PGE Following the procedure of Example 24, l5-methyl- 'l5(R)-PGF B is oxidized to l5-methyl-15(R)-PGE Example 29 l5-Methyl-.l5(R)-PGE Following theprocedure of Example 24, IS-methyl- Example 30 Dihydro-l5(R)-PGE,

, Following the procedure of Example 24, dihydrol 5- methyl-(R)-PGF k! is oxidized to dihydro-l5- methyl-l 5(R)- PGE Following the procedure of Example 24, lS-methyl- 15- rnethyl l5(R)-PGF- a IS-methyI-PGF a l5- methyl-l5(R)-PGF a dihydro-l5-methyl-PGF anddihydro-lS-methyl-15(R)-PGF a are each oxidized to the corresponding PGE compound. 2

Also following the procedure of Example 24, the

methyl, ethyl, tert-b ut'yl, and 2-ethyl-hexyl esters of 15- methyl-PGE or l.5 -methyl-l5(R)-PGE ester. 7 Also following the procedure of Example 24, the

, dihydrO-IS-methyl-PGF, dihydro-lS-methyll5(R)-PGF 01 and clihydro-l5-methyl-l5(R)-PGF [3 and the methyl, ethyl, tert-butyl and 2-ethylhexyl esters of each of those racemic acids are each oxidized to the corresponding racemic IS-methyI-PGE or 15- methyl-15(R)PGF acid or ester.

Also following the procedure of Example 24, I5- ethyl-PGF a l5-ethylPGF B l5-ethyl-l5(R)- PGF, (1 l5-ethyl-l5(R)-PGF|B IS-ethyI-PGF," l5(R)-PGF2 B. l5-ethyl-l5-PGF a. IS-ethyHGE. B, l5-ethyl-l5(R)-PGF a. l5-ethyl-'l5(R)-PGF3 B. dihydro-lS-ethyl-PGF, a, dihydro-IS-ethyI-PGF B, dihydro-l5-ethyl-l5(R)-PGF a, dihydro-lS-ethyll5(R)-PGF [3, and theracemic forms of each of those optically active acids, and the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of each of those optically active and racemic acids are each oxidized to the corresponding IS-ethyl-PGE or l5-ethyll5(R)-PGE acid or ester.

I claim:

1. An optically active compound of the formula:

llO

' COOR IIO UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. :7 Dated April 7: 973

Inventor(s) Gordon L. Bundy It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 5, l ine 55, 'such as athercoscleros is" should read such as atherosclerosis Column 8, lines 56-57, corresponding PGF OL-type or PGF g-type acids" should read corresponding PGF -type or PGFg-type acids Column 12,

l ine 45, Silylation or Organic Compounds," should read "Silylation of Organic Compounds," Column 20, line 11, "mixture of 15-methyl-PGF should read mixture of 15-methyl PGF g Column 21, l ines 49-50, "15-oxo-PGF 15-oxo-PGF should read 15-oxo-PGF 15-oxo-PGF 5, 15-oxo-PGF Column 22, l ine 58, oxidized to 15-methyl-PGF should read oxidized to 15-methyl -PGE Column 24, l ines 5-6, "or 15-methyl -15(R)PGF acid" shou ld read or l5-methyl -15(R)-PGE acid lines -10, "l5-ethyl-PGF 15(R)-PGF 5, l5-ethyl-15- PGFgq, l5-ethyl-PGF should read l5-ethyl-PGF 15-ethyl- Pei- 15-ethyl-15(R)PGF l5-ethyl-l5(R)-PGF 5, l5-ethyl- PGF 15-ethyl -PGF 5, l ine 58, "Racemic 15-methyl -PGF should read 5. Racemic 15-methyl -PGF Signed and Scaled this thirtieth Day of Augus! I977 [SEAL] Atlest.

RUTH C. MASON C. MARSHALL DANN Aliesling ff Commissioner of Patents and Trademarks 

2. 15-Methyl-PGF2 , an optically active compound according to claim 1 wherein R1 is hydrogen and R2 is methyl. Racemic 15-methyl-PGF2 , a compound according to claim 1 wherein R1 is hydrogen and R2 is methyl. 